This project is based on our discovery that genetic mutations in molecules that control the programmed death, or apoptosis, of lymphocytes underlie the Autoimmune Lymphoproliferative Syndrome (ALPS). ALPS is a disease affecting children in which a loss of normal lymphocyte homeostasis leads to swollen lymph glands and organs. Because lymphocytes are the primary cells mediating immune reactions, this excess of lymphocytes leads to a pathological autoimmune attack on the patient's own tissues. We have identified mutations in a death-inducing cell surface receptor termed Fas (also known as APO-1 or CD95) and, in the past year, proteolytic enzymes that are crucial to lymphocyte programmed cell death. These studies promise to provide new insights into the molecular mechanisms that underly autoimmune disease as well as revealing crucial steps in the pathway of programmed cell death in lymphocytes.